1. Field of the Invention
This invention relates generally to nuclear matrix proteins and specifically to novel nuclear matrix proteins with defined tissue expression patterns in normal cells and cells associated with cell proliferative disorders.
2. Description of Related Art
Advances in recombinant DNA technology have led to the discovery of normal cellular genes (proto-oncogenes and tumor suppressor genes) which control growth, development, and differentiation. Under certain circumstances, regulation of these genes is altered and normal cells assume neoplastic growth behavior. In some cases, the normal cell phenotype can be restored by various manipulations associated with these genes. There are over 40 known proto-oncogenes and suppressor genes to date, which fall into various categories depending on their functional characteristics. These include, 1) growth factors and growth factor receptors, 2) messengers of intracellular signal transduction pathways, for example, between the cytoplasm and the nucleus, and 3) regulatory proteins influencing gene expression and DNA replication, located both within and outside the nucleus.
During their life span, normal cells begin in an immature state with proliferative potential, pass through sequential stages of differentiation, and eventually end in cell death. Cancer, on the other hand, is a multistep process which can be defined in terms of stages of malignancy wherein the normal orderly progression is aberrant, probably due to alterations in oncogenes, tumor suppressor genes, and other genes. Research on oncogenes and their products has led to a more fundamental understanding of the mechanisms of cancer causation and maintenance allowing more rational means of diagnosing and treating malignancies.
Genes associated with the control of normal growth and differentiation of cells include genes which encode regulatory proteins which influence gene expression and DNA replication. The gene products of many of these genes localize in the nucleus and many are DNA binding proteins. The nucleus of an animal cell contains cellular DNA complexed with protein, referred to as chromatin. The chromatin is organized by the internal skeleton of the nucleus, called the nuclear matrix. Nuclear matrix proteins (NMP) associated with DNA may be growth/differentiation regulatory proteins which play a role in the regulation of gene expression in a cell. In cells that have lost their growth regulatory mechanisms, it can be envisioned that a nucleus-specific protein may continuously activate a transcriptional promoter region of a gene, causing over-expression of the gene. Similarly, a nuclear protein which functions as a suppressor to control or suppress the expression of various proto-oncogenes, may be under-expressed or expressed in a mutant form, thereby allowing aberrant expression of a gene which otherwise would be suppressed.
Current cancer tests are generally nonspecific, insensitive and, consequently, of limited clinical application. For example, a biochemical test, widely used for both diagnostic and monitoring of cancer, measures levels of carcinoembryonic antigen (CEA). CEA is an oncofetal antigen detectable in large amounts in embryonal tissue, but in small amounts in normal adult tissues. Serum of patients with certain gastrointestinal cancers contains elevated CEA levels that can be measured by immunological methods. The amount of CEA in serum correlates with the remission or relapse of these tumors, with the levels decreasing abruptly after surgical removal of the tumor. The return of elevated CEA levels signifies a return of malignant cells. CEA, however, is also a normal glycoprotein found at low levels in nearly all adults. Moreover, this protein can be elevated with several nonmalignant conditions and is not elevated in the presence of many cancers. Therefore it is far from ideal as a cancer marker. A similar oncofetal tumor marker is alpha-fetoprotein, an embryonic form of albumin. Again, the antigen is detectable in high amounts in embryonal tissue and in low amounts in normal adults. It is elevated in a number of gastrointestinal malignancies including hepatoma. Like CEA, a decrease correlates with the remission of cancer and a re-elevation with relapse. There is insufficient sensitivity and specificity to make this marker useful for screening for malignancy or for monitoring previously diagnosed cancer in any but a few selected cases.
In view of the foregoing, there remains a need for new cancer markers which would allow more effective diagnosis, prognosis and treatment regimes. The identification of NMPs which are associated with the regulation of gene expression or cellular structure in normal and cancer cells would provide ideal markers for identification of the stage of malignancy of a cell.